Gut Epithelial-derived CXCL9 Maintains Gut Homeostasis Through Preventing Overgrown E. coli

• Published in: Journal of Crohn's and colitis Vol. 16; no. 6; pp. 963 - 977
• Main Authors: Wei, Jianmei, Zhang, Chunze, Gao, Yunhuan, Li, Yuanyuan, Zhang, Qianjing, Qi, Houbao, Jin, Mengli, Yang, Xiaorong, Su, Xiaomin, Zhang, Yuan, Yang, Rongcun
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 14.07.2022
• Subjects: gut epithelial cells; CXCL9; aceE; E. coli
• ISSN: 1873-9946; 1876-4479
• DOI: 10.1093/ecco-jcc/jjab234

Abstract Background and Aims Increased E. coli in the colon are related to the occurrence and development of multiple diseases. Chemokines are shown to possess potential antimicrobial activity, including against Gram-positive and -negative bacterial pathogens. We here investigated function[s] of chemokine CXCL9 expressed in the gut epithelial cells, and mechanism[s] of CXCL9 by which to kill E. coli. Methods We generated CXCL9fl/flpvillin-creT mice [pvillin-cre positive mice] and their control CXCL9fl/flpvillin-crewmice [pvillin-cre negative mice], and then employed a dextran sulphate sodium [DSS]-mediated colitis model to determine the sensitivity of CXCL9fl/flpvillin-creT mice. We analysed the composition of the gut microbiota by using 16S ribosomal RNA [V3-V4 variable region] sequencing and shotgun metagenomic analyses. We generated E. coli ΔFtsX [FtsX-depleted E. coli] and E. coli ΔaceE [aceE-depleted E. coli] by using a bacterium red recombining system to investigate the mechanism[s] of CXCL9 by which to kill E. coli. Results CXCL9 fl/flpvillin-creTmice were more sensitive to chemically induced colitis than their control littermates, CXCL9fl/flpvillin-crewmice. After DSS treatment, there were markedly increased gut E. coli [Escherichia-Shigella] in the colonic contents of CXCL9fl/flpvillin-creT mice as compared with control CXCL9fl/flpvillin-crew mice. The increased E. coli could promote colitis through NLRC4 and caspase 1/11-mediated IL-18, which was derived from gut epithelial cells. We finally demonstrated that CXCL9 expressed in gut epithelial cells could kill the overgrown E. coli. E. coli expressed Ftsx and PDHc subunits aceE. E.coliΔaceE but not E. coliΔFtsX were resistant to CXCL9-mediated killing. Conclusions Gut epithelial cells-derived CXCL9 can kill the expanded E. coli through aceE, to remain gut homeostasis. Graphical Abstract